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Prevention and Control of Influenza

Recommendations of the Advisory Committee on Immunization
Practices (ACIP)

Please note:
An erratum has been published for this article. To view the erratum,
please click here.

The material is this report originated in the National Center for Infectious Diseases, James M. Hughes, M.D., Director, and the Division of Viral
and Rickettsial Diseases, James LeDuc, Ph.D., Director; and the National Immunization Program, Walter A. Orenstein, M.D., Director, and
Epidemiology and Surveillance Division, Melinda Wharton, M.D., Director.

Summary

This report updates the 2002 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use
of influenza vaccine and antiviral agents (CDC. Prevention and Control of Influenza: Recommendations of the
Advisory Committee on Immunization Practices [ACIP]. MMWR 2002;51[No.
RR-3]:1--31). The 2003 recommendations include new or updated information regarding 1) the timing of influenza vaccination by age and risk group; 2)
influenza vaccine for children aged 6--23 months; 3) the 2003--2004 trivalent inactivated vaccine virus strains:
A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like antigens (for the
A/Moscow/10/99 [H3N2]-like antigen, manufacturers will use the antigenically equivalent A/Panama/2007/99 [H3N2] virus, and for the
B/Hong Kong/330/2001-like antigen, manufacturers will use either B/Hong Kong/330/2001 or the antigenically equivalent
B/Hong Kong/1434/2002); 4) availability of certain influenza vaccine doses with reduced thimerosal content, including
single 0.25 mL-dose syringes; and 5) manufacturers of influenza vaccine for the U.S. market. Although the optimal time to
vaccinate against influenza is October and November, vaccination in December and later continues to be strongly recommended. A
link to this report and other information regarding influenza can be accessed at
http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

Introduction

Epidemics of influenza typically occur during the winter months and have been responsible for an average of
approximately 36,000 deaths/year in the United States during 1990--1999
(1). Influenza viruses also can cause pandemics, during which
rates of illness and death from influenza-related complications can increase dramatically worldwide. Influenza
viruses cause disease among all age groups
(2--4). Rates of infection are highest among children, but rates of serious illness and death are
highest among persons aged >65 years and persons of any age who have medical conditions that place them at increased risk
for complications from influenza (2,5--7).

Influenza vaccination is the primary method for preventing influenza and its severe complications. In this report from
the Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination
are 1) groups that are at increased risk for influenza-related complications (e.g., persons aged
>65 years and persons of any age with certain chronic medical conditions); 2) the group aged 50--64 years because this group has an elevated prevalence
of certain chronic medical conditions; and 3) persons who live with or care for persons at high risk (e.g., health-care workers
and household contacts who have frequent contact with persons at high risk and who can transmit influenza to persons at
high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all
age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism
among
adults (8--18). Although influenza vaccination levels increased substantially during the 1990s, further improvements in
vaccine coverage levels are needed, chiefly among persons aged <65 years who are at increased risk for influenza-related
complications among all racial and ethnic groups and among blacks and Hispanics aged
>65 years. ACIP recommends using strategies
to improve vaccination levels, including using reminder/recall systems and standing orders programs
(19,20). Although influenza vaccination remains the cornerstone for the control and treatment of influenza, information is also presented
regarding antiviral medications, because these agents are an adjunct to vaccine.

Primary Changes and Updates in the Recommendations

The 2003 recommendations include five principal changes or updates:

The optimal time to receive influenza vaccine continues to be October and November. However, because of
vaccine distribution delays during 2000--2002, ACIP recommends that vaccination efforts in October focus on persons aged
>50 years and those aged 6--23 months, persons aged 2--49 years with certain medical conditions that place them at
increased risk for influenza-related complications, children aged <9 years receiving influenza vaccine for the first time,
health-care workers, and household contacts of persons at high risk, and that vaccination of other groups begin in November.

Because young, otherwise healthy children are at increased risk for influenza-related hospitalization, influenza
vaccination of healthy children aged 6--23 months continues to be encouraged when feasible. Vaccination of children aged
>6 months who have certain medical conditions continues to be strongly recommended.

The 2003--2004 trivalent inactivated vaccine virus strains are A/Moscow/10/99 (H3N2)-like, A/New
Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like antigens (for the A/Moscow/10/99 [H3N2]-like antigen,
manufacturers will use the antigenically equivalent
A/Panama/2007/99 [H3N2] virus, and for the B/Hong Kong/330/2001-like
antigen, manufacturers will use either B/Hong Kong/330/2001 or the antigenically equivalent B/Hong Kong/1434/2002).

A limited amount of influenza vaccine with reduced thimerosal content, including 0.25-mL single-dose
syringe preparations for children aged 6--35 months, should be available for the 2003--04 influenza season.

Influenza vaccine for the U.S. market will be available from two manufacturers in 2003--04, compared with
three manufacturers in 2002--03.

Influenza and Its Burden

Biology of Influenza

Influenza A and B are the two types of influenza viruses that cause epidemic human disease
(21). Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza
B viruses are not categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and
influenza B viruses have been in global circulation. In 2001, influenza A (H1N2) viruses that probably emerged
after genetic reassortment between human A (H3N2) and A (H1N1) viruses began circulating widely. Both influenza A and
B viruses are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result
from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication.
Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.

A person's immunity to the surface antigens, including
hemagglutinin, reduces the likelihood of infection and severity
of disease if infection occurs (22). Antibody against one influenza virus type or subtype confers limited or no protection
against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new
antigenic variant of the same type or subtype
(23). Frequent development of antigenic variants through antigenic drift is the virologic basis
for seasonal epidemics and the reason for the usual incorporation of
>1 new strains in each year's influenza vaccine.

Clinical Signs and Symptoms of Influenza

Influenza viruses are spread from person to person primarily through the coughing and sneezing of infected persons
(21). The incubation period for influenza is 1--4 days, with an average of 2 days
(24). Adults typically are infectious from the
day before symptoms begin through approximately 5 days
after illness onset. Children can be infectious for
>10 days, and young children can shed virus for
<6 days before their illness onset. Severely immunocompromised persons can shed virus for
weeks or months (25--28).

Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and
symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat, and rhinitis)
(29). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness
(30--32). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone (see
Role of Laboratory Diagnosis). Reported sensitivities and specificities of clinical definitions for influenza-like illness in
studies primarily among adults that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively,
compared with viral culture (33,34). Sensitivity and predictive value of clinical definitions can vary, depending on the degree of
co-circulation of other respiratory pathogens and the level of influenza activity
(35). A study among older nonhospitalized patients determined that symptoms of fever, cough, and acute onset had a positive predictive value of 30% for influenza
(36), whereas a study of hospitalized older patients with chronic cardiopulmonary disease determined that a combination of
fever, cough, and illness of <7 days was 78% sensitive and 73% specific for influenza
(37). However, a study among vaccinated
older persons with chronic lung disease reported that cough was not predictive of influenza infection, although having a fever
or feverishness was 68% sensitive and 54% specific for influenza infection
(38).

Influenza illness typically resolves after a limited number of days for the majority of persons, although cough and malaise
can persist for >2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary
or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a
coinfection with other viral or bacterial pathogens
(39). Young children with influenza infection can have initial symptoms
mimicking bacterial sepsis with high fevers
(40,41), and <20% of children hospitalized with influenza can have febrile seizures
(31,42). Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis,
myocarditis, and pericarditis (31,39,43,44).

Hospitalizations and Deaths from Influenza

The risks for complications, hospitalizations, and deaths from influenza are higher among persons aged
>65 years, young children, and persons of any age with certain underlying health conditions (see Persons at Increased Risk for
Complications) than among healthy older children and younger adults
(1,6,8,45--50). Estimated rates of influenza-associated
hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics (Table 1).

Among children aged 0--4 years, hospitalization rates have ranged from approximately 500/100,000 population for
those with high-risk medical conditions to 100/100,000 population for those without high-risk medical conditions
(51--54). Within the 0--4 age group, hospitalization rates are highest among children aged 0--1 years and are comparable to
rates reported among persons >65 years
(53,54) (Table 1).

During influenza epidemics from 1969--70 through 1994--95, the estimated overall number of
influenza-associated hospitalizations in the United States ranged from approximately 16,000 to 220,000/epidemic. An average of
approximately 114,000 influenza-related excess hospitalizations occurred per year, with 57% of all hospitalizations occurring among
persons aged <65 years. Since the 1968 influenza A (H3N2)
virus pandemic, the greatest numbers of
influenza-associated hospitalizations have occurred during epidemics caused by type A (H3N2) viruses, with an estimated average of
142,000 influenza-associated hospitalizations per year
(55).

Influenza-related deaths can result from pneumonia as well as from exacerbations of cardiopulmonary conditions and
other chronic diseases. Older adults account for
>90% of deaths attributed to pneumonia and influenza
(1,50). In a recent study of influenza epidemics, approximately 19,000
influenza-associated pulmonary and circulatory deaths per influenza
season occurred during 1976--1990, compared with approximately 36,000 deaths during 1990--1999
(1). Estimated rates of influenza-associated pulmonary and circulatory deaths/100,000 persons were 0.4--0.6 among persons aged 0--49 years,
7.5 among persons aged 50--64 years, and 98.3 among persons aged
>65 years. In the United States, the number of
influenza-associated deaths might be increasing in part
because the number of older persons is increasing
(56). In addition, influenza seasons in which influenza A (H3N2)
viruses predominate are associated with higher mortality
(57); influenza A (H3N2) viruses predominated in 90% of influenza seasons from 1990--1999, compared with 57% of
seasons from 1976--1990 (1).

Options for Controlling Influenza

In the United States, the primary option for reducing the effect of influenza is immunoprophylaxis with inactivated
(i.e., killed virus) vaccine (see Recommendations for Using Inactivated Influenza Vaccine). Vaccinating persons at high risk
for
complications each year before seasonal increases in influenza virus circulation is the most effective means of reducing
the effect of influenza. Vaccination coverage can be increased by administering vaccine to persons during hospitalizations
or routine health-care visits before the influenza season, making special visits to physicians' offices or clinics unnecessary.
When vaccine and epidemic strains are well-matched, achieving
increased vaccination rates among persons living in closed
settings (e.g., nursing homes and other chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing
herd immunity (13). Vaccination of health-care workers and other persons in close contact with persons at increased risk for
severe influenza illness can also reduce transmission of
influenza and subsequent influenza-related complications.
Antiviral drugs used for chemoprophylaxis or treatment of influenza are a key adjunct to vaccine (see Recommendations for Using
Antiviral Agents for Influenza). However, antiviral medications are not a substitute for vaccination.

Inactivated Influenza Vaccine Composition

Inactivated influenza vaccines are standardized to contain the hemagglutinins of strains (i.e., typically two type A and
one type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter. The vaccine is
made from highly purified, egg-grown viruses that have been made noninfectious (i.e., inactivated or killed)
(58). Subvirion and purified surface antigen preparations are available.
Because the vaccine viruses are initially grown in embryonated hens'
eggs, the vaccine might contain limited amounts of
residual egg protein.

Manufacturing processes differ by manufacturer. Manufacturers might use different compounds to inactivate
influenza viruses and add antibiotics to prevent bacterial contamination. Package inserts should be consulted for additional
information.

Inactivated influenza vaccine distributed in the United States might also contain thimerosal, a
mercury-containing compound, as the preservative
(59,60). Thimerosal has been used as a preservative in vaccines since the 1930s. Although
no evidence of harm caused by low levels of thimerosal in vaccines has been reported, in 1999, the U.S. Public Health Service
and other organizations recommended that efforts be made to reduce the thimerosal content in vaccines to decrease total
mercury exposure, chiefly among infants and pregnant woman
(59,61). Since mid-2001, routinely administered,
noninfluenza childhood vaccines for the U.S. market have been manufactured either without or with only trace amounts of thimerosal
to provide a substantial reduction in the total mercury
exposure from vaccines for children (62).

For the 2003--04 influenza season, a limited number of
individually packaged doses (i.e., single-dose syringes)
of preservative-free influenza vaccine (<1 mcg mercury/0.5 mL dose) will be available, including single-dose vaccine packaged
in doses of 0.5 mL (dose for persons aged
>3 years) and 0.25 mL (dose for children 6--35 months). Reduced
thimerosal-content vaccine is available both from Evans Vaccines, Ltd. (FDA-approved for persons aged
>4 years) and from Aventis Pasteur (FDA-approved for persons aged
>6 months) (see Inactivated Influenza Vaccine Use For Young Children, By
Manufacturer). Multidose vials and single-dose syringes of influenza vaccine containing approximately 25 mcg
thimerosal/0.5 mL dose are also available, as they have been in previous years. Because of the known risks of severe illness from influenza infection and
the benefits of vaccination and because a substantial safety margin has been incorporated into the health guidance values
for organic mercury exposure, the benefit of influenza vaccine with reduced or standard thimerosal content outweighs
the theoretical risk, if any, from thimerosal
(59,63). The removal of thimerosal from other vaccines further reduces the
theoretical risk from thimerosal in influenza vaccines.

The trivalent inactivated influenza vaccine prepared for the 2003--04 season will include A/Moscow/10/99 (H3N2)-like,
A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like antigens. For the A/Moscow/10/99
(H3N2)-like antigen, manufacturers will use the antigenically equivalent A/Panama/2007/99 (H3N2) virus, and for the B/Hong
Kong/330/2001-like antigen, manufacturers will use either B/Hong Kong/330/2001 or the antigenically equivalent B/Hong
Kong/1434/2002. These viruses will be used because of their growth properties and because they are representative of
influenza viruses likely to circulate in the United States during the 2003--04 influenza season. Because circulating influenza A
(H1N2) viruses are a reassortant of influenza A (H1N1) and (H3N2) viruses, antibody directed against influenza A (H1N1)
and influenza (H3N2) vaccine strains will provide protection against circulating influenza A (H1N2) viruses.

Effectiveness of Inactivated Influenza Vaccine

The effectiveness of influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and
the degree of similarity between the viruses in the vaccine and those in circulation. The majority of vaccinated children and
young adults develop high postvaccination hemagglutination inhibition antibody titers
(64--66). These antibody titers are
protective against illness caused by strains similar to those in the vaccine
(65--68).

Adults Aged <65 Years. When the vaccine and circulating viruses are antigenically similar, influenza vaccine
prevents influenza illness in approximately 70%--90% of healthy adults aged <65 years
(9,12,69,70). Vaccination of healthy adults
also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when
the vaccine and circulating viruses are well-matched
(9--12,70,71).

Children. Children aged as young as 6 months can develop protective levels of antibody after influenza
vaccination (64,65,72--75), although the antibody response among children at high risk of influenza-related complications might be
lower than among healthy children (76,77). In a randomized study among children aged 1--15 years, inactivated influenza
vaccine was 77%--91% effective against influenza respiratory illness and was 44%--49%, 74%--76%, and 70%--81% effective
against influenza seroconversion among children aged
1--5, 6--10, and 11--15 years, respectively
(66). One study (78) reported a vaccine efficacy of 56% against influenza illness
among healthy children aged 3--9 years and anther study
(79) determined vaccine efficacy of 22%--54% and 60%--78% among children with asthma aged 2--6 years and 7--14 years, respectively. A
2-year randomized study of children aged 6--24 months determined that
>89% of children seroconverted to all three
vaccine strains during both years (80). During year 1, among 411 children, vaccine efficacy was 66% (95% confidence interval [CI]
= 34% and 82%) against culture-confirmed influenza (attack rates: 5.5% and 15.9% among vaccine and placebo
groups). During year 2, among 375 children, vaccine efficacy was --7% (95% CI = --247% and 67%; attack rates: 3.6% and
3.3% among vaccine and placebo groups). However, no overall reduction in otitis media was reported
(80). Other studies report that trivalent inactivated influenza
vaccine decreases the incidence of influenza-associated otitis media among young children
by approximately 30% (16,17).

Adults Aged >65 years of Age. Older persons and persons with certain chronic diseases might develop
lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza-related
upper respiratory tract infection (81--83). A randomized trial among noninstitutionalized persons aged
>60 years reported a vaccine efficacy of 58% against influenza respiratory illness, but indicated that efficacy might be lower among those aged
>70 years (84). The vaccine can also be effective in preventing secondary complications and reducing the risk for
influenza-related hospitalization and death among adults
>65 years with and without high-risk medical conditions (e.g., heart
disease and diabetes) (13--15,18,85). Among elderly persons living outside of nursing homes or similar chronic-care
facilities, influenza vaccine is 30%--70% effective in preventing hospitalization for pneumonia and influenza
(15,86). Among elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary
complications, and deaths. Among this population, the vaccine can be 50%--60% effective in preventing hospitalization or pneumonia
and 80% effective in preventing death, although the effectiveness in preventing influenza illness often ranges from 30% to
40% (87--89).

Cost-Effectiveness of Influenza Vaccine

Influenza vaccination can reduce both health-care costs and productivity losses associated with influenza illness.
Economic studies of influenza vaccination of persons aged
>65 years conducted in the United States have reported overall societal
cost savings and substantial reductions in hospitalization and death
(15,86,90). Studies of adults aged <65 years have reported
that vaccination can reduce both direct medical costs and
indirect costs from work absenteeism
(8,10--12,70,91). Reductions of 34%--44% in physician visits, 32%--45% in lost workdays
(10,12), and 25% in antibiotic use for
influenza-associated illnesses have been reported
(12). One cost-effectiveness analysis estimated a cost of approximately $60--$4,000/illness
averted among healthy persons aged 18--64 years, depending on the cost of vaccination, the influenza attack rate, and
vaccine effectiveness against influenza-like illness
(70). Another cost-benefit economic model estimated an average annual savings
of $13.66/person vaccinated (92). In the second study, 78% of all costs prevented were costs from lost work productivity,
whereas the first study did not include productivity losses from influenza illness. Economic studies specifically evaluating the
cost-effectiveness of vaccinating persons aged 50--64 years are not available, and the number of studies that examine the
economics of routinely vaccinating children are limited
(8,93--95). However, in a study that included
all age groups, cost utility improved with increasing age and among those with chronic medical conditions
(8). Among persons aged >65 years, vaccination
resulted in a net savings per quality-adjusted life year (QALY) gained and
resulted in costs of $23--$256/QALY among younger
age groups. Additional studies of the relative cost-effectiveness and cost utility of influenza vaccination among children and
among adults aged <65 years are needed and should be designed to account for year-to-year variations in influenza attack rates,
illness severity, and vaccine efficacy when evaluating the long-term costs and benefits of annual vaccination.

Vaccination Coverage Levels

Among persons aged >65 years, influenza vaccination levels increased from 33% in 1989
(96) to 66% in 1999 (97), surpassing the
Healthy People 2000 objective of 60%
(98). Vaccine coverage reached the highest levels recorded (68%)
during the 1999--00 influenza season, using the percentage of adults reporting influenza vaccination during the past 12 months
who participated in the National Health Interview Survey (NHIS) during the first and second quarters of each calendar year as
a proxy measure of influenza vaccine coverage for the previous influenza season
(97). Possible reasons for the increase in influenza vaccination levels among persons aged
>65 years through the 1999--00 influenza season include
1) greater acceptance of preventive medical services by
practitioners; 2) increased delivery and administration of vaccine by
health-care providers and sources other than physicians; 3) new information regarding influenza vaccine effectiveness,
cost-effectiveness, and safety; and 4) the initiation of Medicare reimbursement for influenza vaccination in 1993
(8,14,15,87,88,99,100). Vaccine coverage increased more rapidly through the mid-1990s than during subsequent
seasons (average annual percentage increase of 4% from 1988--89 to 1996--97 versus 1% from 1996--97 to 1999--00).

Estimated influenza vaccination coverage for the 2000--01 influenza season was lower than for the previous season
among adults aged >65 years (64% versus 68%) and adults aged 50--64 years (32% versus 38%)
(97). Delays in influenza vaccine supply during fall 2000 probably contributed to these declines in vaccination levels (see Inactivated Influenza Vaccine
Supply). Estimated vaccine coverage for the 2001--02 season, during which less severe influenza vaccine supply delays occurred,
were equivalent to 1999--00 season estimates (67% for adults aged
>65 years and 35% for adults aged 50--64 years).
Continued annual monitoring is needed to determine the effects of vaccine supply delays and other factors on vaccination coverage
among persons aged >50 years. The Healthy People
2010 objective is to achieve vaccination coverage for 90% of
persons aged >65 years (101).

Reducing racial and ethnic health disparities, including disparities in vaccination coverage, is an overarching national
goal (101). Although estimated influenza vaccination coverage for the 1999--00 season reached the highest levels recorded
among older black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind
those among whites (97,102). Estimated influenza vaccination levels for the 2001--02 season among persons aged
>65 years were 70% among non-Hispanic whites, 52% among non-Hispanic blacks, and 47% among Hispanics
(97). Additional strategies are needed to achieve the
Healthy People 2010 objective among all racial and ethnic groups.

In 1997 and 1998, vaccination coverage estimates among nursing home residents were 64%--82% and 83%,
respectively (103,104). The Healthy People
2010 goal is to achieve influenza vaccination of 90% of nursing home residents,
an increase from the Healthy People 2000 goal of 80%
(98,101).

For the 2000--01 influenza season, the estimated vaccination coverage among adults aged 18--64 years with
high-risk conditions was 29%, substantially lower than the
Healthy People 2000 and 2010 objective of 60% (unpublished data,
National Immunization Program [NIP], CDC, 2003)
(98,101). Among persons aged 50--64 years, 41% of those with chronic
medical conditions and 29% of those without chronic medical conditions received influenza vaccine. Only 21% of adults aged
<50 years with high-risk conditions were vaccinated.

Reported vaccination levels are low among children at
increased risk for influenza complications. One study
conducted among patients in health maintenance organizations reported influenza vaccination percentages ranging from 9% to
10% among children with asthma (105). A 25% vaccination level was reported among children with severe to moderate
asthma who attended an allergy and immunology clinic
(106). However, a study conducted in a pediatric clinic demonstrated
an increase in the vaccination percentage of children with asthma or reactive airways disease from 5% to 32% after
implementing a reminder/recall system (107). One study reported 79% vaccination coverage among children attending a cystic
fibrosis treatment center (108). Increasing vaccination coverage among persons who have high-risk conditions and are aged <65
years, including children at high risk, is the highest priority for expanding influenza vaccine use.

Annual vaccination is recommended for health-care workers. Nonetheless, NHIS reported vaccination coverage of only
34% and 36% among health-care workers in the 1997 and 2001 surveys, respectively
(109) (unpublished NHIS data, NIP, CDC, 2003). Vaccination of health-care workers has been
associated with reduced work absenteeism (9) and fewer deaths
among nursing home patients (110,111).

Limited information is available regarding using influenza vaccine among pregnant women. Among women aged
18--44 years without diabetes responding to the 2001 Behavioral Risk Factor Surveillance System, those reporting they were
pregnant were less likely to report influenza vaccination during the past 12 months (13.7%) than those not pregnant (16.8%)
(112).
However, vaccination coverage was slightly higher than in 1997 when 11.2% of pregnant and 14.4% of nonpregnant
women were vaccinated. Similar results were determined by using the 1997--2001 NHIS data, excluding pregnant women
who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (unpublished NHIS data, NIP,
CDC, 2002). Although not directly measuring influenza vaccination among women who were past the first trimester of
pregnancy during influenza season, these data indicate low compliance with the ACIP recommendations for pregnant women. In a
study of influenza vaccine acceptance by pregnant women, 71% who were offered the vaccine chose to be vaccinated
(113). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine
to obstetric patients, although 86% agreed that pregnant women's risk for influenza-related morbidity and mortality
increases during the last two trimesters
(114).

Recommendations for Using Inactivated Influenza Vaccine

Influenza vaccine is strongly recommended for any person aged
>6 months who is at increased risk for complications
from influenza. In addition, health-care workers and other persons (including household members) in close contact with persons
at high risk should be vaccinated to decrease the risk for transmitting influenza to persons at high risk. Influenza vaccine also
can be administered to any person aged >6 months to reduce the chance of becoming infected with influenza.

Target Groups for Vaccination

Persons at Increased Risk for Complications

Vaccination is recommended for the following persons who are at increased risk for complications from influenza:

persons aged >65 years;

residents of nursing homes and other chronic-care facilities that house persons of any age who have
chronic medical conditions;

adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma;

adults and children who have required regular medical follow-up or hospitalization during the preceding year because
of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies,
or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus [HIV]);

children and adolescents (aged 6 months--18 years) who are receiving long-term aspirin therapy and, therefore, might
be at risk for experiencing Reye syndrome after influenza
infection; and

women who will be in the second or third trimester of pregnancy during the influenza season.

In 2000, approximately 73 million persons in the United States fell into
>1 of these target groups, including 35
million persons aged >65 years; and 12 million adults aged 50--64 years, 18 million adults aged 18--49 years, and 8 million
children aged 6 months--17 years with >1 medical conditions that are associated with an increased risk for
influenza-related complications (115).

Persons Aged 50--64 Years

Vaccination is recommended for persons aged 50--64 years because this group has an increased prevalence of persons
with high-risk conditions. In 2000, approximately 42 million persons in the United States were aged 50--64 years, of whom
12 million (29%) had >1 high-risk medical conditions
(115). Influenza vaccine has been recommended for this entire age
group to increase the low vaccination rates among persons in this age group with high-risk conditions. Age-based strategies are
more successful in increasing vaccine coverage than
patient-selection strategies based on medical conditions. Persons aged
50--64 years without high-risk conditions also receive benefit from vaccination in the form of decreased rates of influenza
illness, decreased work absenteeism, and decreased need for medical visits and medication, including antibiotics
(9--12). Further, 50 years is an age when other preventive services
begin and when routine assessment of vaccination and other preventive
services has been recommended (116,117).

Persons Who Can Transmit Influenza to Those at High Risk

Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for
complications from influenza. Decreasing transmission of influenza from caregivers and household contacts to persons at high risk
might reduce influenza-related deaths among persons at high risk. Evidence from two studies indicates that vaccination of
health-care personnel is associated with decreased deaths among nursing home patients
(110,111). Vaccination of health-care
personnel and others in close contact with persons at high risk, including household contacts, is recommended.

The following groups should be vaccinated:

physicians, nurses, and other personnel in both hospital and outpatient-care settings, including medical
emergency response workers (e.g., paramedics and emergency
medical technicians);

employees of nursing homes and chronic-care facilities who have contact with patients or residents;

employees of assisted living and other residences for
persons in groups at high risk;

persons who provide home care to persons in groups at high risk; and

household contacts (including children) of persons in groups at high risk.

In addition, because children aged 0--23 months are at
increased risk for influenza-related hospitalization
(52--54), vaccination is encouraged for their household contacts and out-of-home caregivers, particularly for contacts of children aged 0--5
months because influenza vaccines have not been approved by the U.S. Food and Drug Administration (FDA) for use among
children aged <6 months (see Healthy Young Children).

Additional Information Regarding Vaccination of Specific Populations

Pregnant Women

Influenza-associated excess deaths among pregnant women were documented during the pandemics of 1918--19 and
1957--58 (118--121). Case reports and limited studies also indicate that pregnancy can increase the risk for serious
medical complications of influenza
(122--126). An increased risk might result from increases in heart rate, stroke volume, and
oxygen consumption; decreases in lung capacity; and changes in immunologic function during pregnancy. A study of the impact
of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for
selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14--20
of gestation to 4.7 during weeks 37--42, in comparison with women who were 1--6 months postpartum
(127). Women in their third trimester of pregnancy were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that
of nonpregnant women who had high-risk medical conditions. Researchers estimated that an average of 1--2
hospitalizations could be prevented for every 1,000 pregnant women
vaccinated.

Because of the increased risk for influenza-related complications, women who will be beyond the first trimester of
pregnancy (>14 weeks gestation) during the influenza season should be vaccinated. Certain providers prefer to administer
influenza vaccine during the second trimester to avoid a coincidental association with spontaneous abortion, which is common in
the first trimester, and because exposures to vaccines traditionally have been avoided during the first trimester
(128). Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before
the influenza season, regardless of the stage of pregnancy. A study of influenza vaccination of >2,000 pregnant
women demonstrated no adverse fetal effects associated with influenza vaccine
(129). However, additional data are needed to
confirm the safety of vaccination during pregnancy.

The majority of influenza vaccine distributed in the United States contains thimerosal, a mercury-containing compound,
as a preservative, but influenza vaccine with reduced thimerosal content is available in limited quantities (see
Inactivated Influenza Vaccine Composition). Thimerosal has been used in U.S. vaccines since the 1930s. No data or evidence exists of
any harm caused by the level of mercury exposure that might occur from influenza vaccination. Because pregnant women are
at increased risk for influenza-related complications and because a substantial safety margin has been incorporated into the
health guidance values for organic mercury exposure, the benefit of influenza vaccine with reduced or standard
thimerosal content outweighs the potential risk, if any, for thimerosal
(59,63).

Persons Infected with HIV

Limited information is available regarding the frequency and severity of influenza illness or the benefits of
influenza vaccination among persons with HIV infection
(130,131). However, a retrospective study of young and middle-aged
women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations
among women with HIV infection was higher during influenza seasons than during the peri-influenza periods. The risk
for hospitalization was higher for HIV-infected women than for women with other well-recognized high-risk
conditions, including chronic heart and lung diseases
(132). Another study estimated that the risk for influenza-related death
was 9.4--14.6/10,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.09--0.10/10,000 among
all persons aged 25--54 years and 6.4--7.0/10,000 among persons aged
>65 years (133). Other reports demonstrate that
influenza symptoms might be prolonged and the risk for complications from influenza increased for certain HIV-infected persons
(134--136).

Influenza vaccination has been demonstrated to produce substantial antibody titers against influenza among
vaccinated HIV-infected persons who have minimal AIDS-related symptoms and high
CD4+ T-lymphocyte cell counts
(137--140). A limited, randomized, placebo-controlled trial determined that influenza vaccine was highly effective in
preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected persons with a mean of 400
CD4+ T-lymphocyte cells/mm3; a limited number of persons with
CD4+ T-lymphocyte cell counts of <200 were included in that study
(131). A nonrandomized study among HIV-infected persons determined that influenza vaccination was most effective among
persons with >100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL
(136). Among persons who have advanced HIV disease and low
CD4+ T-lymphocyte cell counts, influenza vaccine might not induce protective antibody
titers (139,140); a second dose of vaccine does not improve the immune response in these persons
(140,141).

One study determined that HIV RNA levels increased transiently in one HIV-infected person after influenza
infection (142). Studies have demonstrated a transient (i.e., 2--4 week) increase in replication of HIV-1 in the plasma or
peripheral blood mononuclear cells of HIV-infected persons after vaccine administration
(139,143). Other studies using similar laboratory techniques have not documented a substantial
increase in the replication of HIV
(144--147). Deterioration of CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIV-infected persons
after influenza vaccination compared with unvaccinated persons
(140,148). Limited information is available concerning the
effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza infection or influenza
vaccination (130,149). Because influenza can result in serious illness and because influenza vaccination can result in the production
of protective antibody titers, vaccination will benefit HIV-infected persons, including HIV-infected
pregnant women.

Breastfeeding Mothers

Influenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does
not adversely affect the immune response and is not a
contraindication for vaccination.

Travelers

The risk for exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza
can occur throughout the year. In the temperate regions of the Southern Hemisphere, the majority of influenza
activity occurs during April--September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can
be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups (e.g., on
cruise ships) that include persons from areas of the world where influenza viruses are circulating
(150,151). Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should
consider receiving influenza vaccine before travel if they plan to

travel to the tropics;

travel with organized tourist groups at any time of year; or

travel to the Southern Hemisphere during
April--September.

No information is available regarding the benefits of revaccinating persons before summer travel who were
already vaccinated in the preceding fall. Persons at high risk who received the previous season's vaccine before travel should
be revaccinated with the current vaccine in the following fall or winter. Persons aged
>50 years and others at high risk might
want
to consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks for
influenza and the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza.

Healthy Young Children

Studies indicate that rates of hospitalization are higher among young children than older children when influenza viruses
are in circulation (51--53,152,153). The increased rates of hospitalization are comparable with rates for other groups considered
at high risk for influenza-related complications. However, the interpretation of these findings has been confounded by
co-circulation of respiratory syncytial viruses, which are a cause of serious respiratory viral illness among children and
which frequently circulate during the same time as influenza viruses
(154--156). Two recent studies have attempted to separate
the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children who do not have
high-risk conditions (52,53). Both studies reported that otherwise healthy children aged <2 years, and possibly children aged
2--4 years, are at increased risk for influenza-related hospitalization compared with older healthy children (Table 1). Among
the Tennessee Medicaid population during 1973--1993, healthy children aged 6 months--<3 years had rates of
influenza-associated hospitalization comparable with or higher than rates among children aged 3--14 years with high-risk
conditions (Table 1) (52,54). Another Tennessee study reported a
hospitalization rate of 3--4/1,000 healthy children aged <2
years/year for laboratory-confirmed influenza
(32).

Because children aged 6--23 months are at substantially
increased risk for influenza-related hospitalizations, ACIP,
the American Academy of Pediatrics, and the American Academy of Family Physicians continue to encourage vaccination of
all children in this age group when feasible
(157). However, the benefits of a full recommendation to vaccinate all children
aged 6--23 months will depend on the identification and implementation of practical and efficient annual influenza
vaccination strategies for providers of health care to children. In the interim, the identification of potential strategies for
influenza vaccination of children, review of additional data from ongoing studies among children aged 6--23 months
receiving influenza vaccine, and efforts to educate parents and providers regarding the impact of influenza and the potential benefits
and risks of vaccinating young children will continue. A full recommendation might be made within a year. ACIP continues
to strongly recommend influenza vaccination of persons aged
>6 months who have high-risk medical conditions.

The current inactivated influenza vaccine is not approved by FDA for use among children aged <6 months, the
pediatric group at greatest risk for influenza-related complications
(52). Vaccinating their household contacts and
out-of-home caregivers might decrease the probability of influenza among these children.

Beginning in March 2003, the group of children eligible for influenza vaccine coverage under the Vaccines for
Children (VFC) program was expanded to include all
VFC-eligible children aged 6--23 months and VFC-eligible children aged
2--18 years who are household contacts of children aged 0--23 months
(158).

General Population

In addition to the groups for which annual influenza vaccination is recommended, physicians should administer
influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered
to children >6 months), depending on vaccine availability (see Inactivated Influenza Vaccine Supply). Persons who
provide essential community services should be considered for vaccination to minimize disruption of essential activities
during influenza outbreaks. Students or other persons in
institutional settings (e.g., those who reside in dormitories) should
be encouraged to receive vaccine to minimize the disruption
of routine activities during epidemics.

Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine

Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs
or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse
Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have
a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications from
influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components
is located in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated
until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate the use of influenza
vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.

Timing of Annual Vaccination with Inactivated Influenza Vaccine

The annual supply of inactivated influenza vaccine and the timing of its distribution cannot be guaranteed in any
year. Information regarding the supply of 2003--04 vaccine might not be available until late summer or early fall 2003.

To allow vaccine providers to plan for the upcoming vaccination season, taking into account the yearly possibility of
vaccine delays or shortages and the need to ensure vaccination of persons at high risk and their contacts, the ACIP recommends
that vaccine campaigns conducted in October should focus their efforts primarily on persons at increased risk for
influenza complications and their contacts, including health-care workers. Campaigns conducted in November and later
should continue to vaccinate persons at high risk and their contacts, but also vaccinate other persons who wish to
decrease their risk for influenza infection. Vaccination efforts for all groups should continue into December and beyond.

Vaccination in October and November

The optimal time to vaccinate is usually during October--November. ACIP recommends that vaccine providers focus
their vaccination efforts in October and earlier primarily on persons aged
>50, persons aged <50 years at increased
risk of influenza-related complications (including children aged 6--23 months), household contacts of persons at high risk (including
out-of-home caregivers and household contacts of children aged 0--23 months), and health-care workers. Vaccination of
children aged <9 years who are receiving vaccine for the first time should also begin in
October because those persons need a booster dose 1 month after the initial dose. Efforts to vaccinate other persons who wish to decrease their risk for influenza
infection should begin in November; however, if such persons request vaccination in October, vaccination should not be
deferred. Materials to assist providers in prioritizing early vaccine are available at
http://www.cdc.gov/nip/flu/Provider.htm
(for information regarding vaccination of travelers, see the travelers section in this report).

Timing of Organized Vaccination Campaigns

Persons planning substantial organized vaccination
campaigns should consider scheduling these events after
mid-October because the availability of vaccine in any location cannot be ensured consistently in the early fall. Scheduling campaigns
after mid-October will minimize the need for cancellations because vaccine is unavailable. Campaigns conducted before
November should focus efforts on vaccination of persons aged
>50 years, persons aged <50 years at increased risk of
influenza-related complications (including children aged 6--23 months), health-care workers, and household contacts of persons at
high-risk (including children aged 0--23 months) to the extent feasible.

Vaccination in December and Later

After November, certain persons who should or want to
receive influenza vaccine remain unvaccinated. In
addition, substantial amounts of vaccine have remained unused during the past three influenza seasons. To improve vaccine
coverage, influenza vaccine should continue to be offered in December and throughout the influenza season as long as vaccine
supplies are available, even after influenza activity has been documented in the community. In the United States, seasonal
influenza activity can begin to increase as early as November or December, but influenza activity has not reached peak levels in
the majority of recent seasons until late December--early March (Table 2). Therefore, although the timing of influenza activity
can vary by region, vaccine administered after November
is likely to be beneficial in the majority of influenza seasons.
Adults develop peak antibody protection against influenza infection 2 weeks after vaccination
(159,160).

Vaccination Before October

To avoid missed opportunities for vaccination of persons at high risk for serious complications, such persons should
be offered vaccine beginning in September during routine health-care visits or during hospitalizations, if vaccine is available.
In facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because
antibody levels in such persons can begin to decline within a limited time after vaccination
(161).

Dosage

Dosage recommendations vary according to age group
(Table 3). Among previously unvaccinated children aged
<9 years, two doses administered >1 month apart are recommended for satisfactory antibody responses. If possible, the second
dose should be administered before December. Among adults, studies have indicated limited or no improvement in
antibody
response when a second dose is administered during the same season
(162--164). Even when the current influenza
vaccine contains >1 antigens administered in previous years, annual vaccination with the current vaccine is
necessary because immunity declines during the year after vaccination
(165,166). Vaccine prepared for a previous influenza
season should not be administered to provide protection for the
current season.

Inactivated Influenza Vaccine Use for Young Children, by Manufacturer

When vaccinating children aged 6 months--3 years, providers should use inactivated influenza vaccine that has
been approved by FDA for this age group. Influenza vaccine from Aventis Pasteur, Inc.,
(Fluzone® split-virus) is approved for
use among persons aged >6 months. Influenza vaccine from Evans Vaccines Ltd.
(Fluvirin®) is labeled in the United States for
use only among persons aged >4 years because data to
demonstrate efficacy among younger persons have not been provided
to FDA.

Route

The intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in
the deltoid muscle. A needle length >1 inches can be considered for these age groups because needles <1 inch might be
of insufficient length to penetrate muscle tissue in certain adults and older children
(167).

Infants and young children should be vaccinated in the
anterolateral aspect of the thigh (62). ACIP recommends a
needle length of 7/8--1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When
injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8--1¼ inches
is recommended (62).

In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination
site (affecting 10%--64% of patients) that lasts <2 days
(12,168--170). These local reactions typically are mild and rarely
interfere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults
and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza
vaccine (25.1%) than placebo-injection (20.8%)
(171). One study (77) reported 20%--28% of asthmatic children aged 9
months--18 years with local pain and swelling and another study
(75) reported 23% of children aged 6 months--4 years with chronic
heart or lung disease had local reactions. A different study
(74) reported no difference in local reactions among 53 children aged
6 months--6 years with high-risk medical conditions or among 305 healthy children aged 3--12 years in a
placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5--32 months, no substantial local or systemic
reactions were noted (172).

Systemic Reactions

Fever, malaise, myalgia, and other systemic symptoms can occur after vaccination and most often affect persons who
have had no prior exposure to the influenza virus antigens in the vaccine (e.g., young children)
(173,174). These reactions begin 6--12 hours after vaccination and can persist for 1--2 days. Recent placebo-controlled trials demonstrate that among
older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of
systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections
(12,168--170).

Less information from published studies is available for children, compared with adults. However, in a randomized
cross-over study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age
group (171). An analysis of 215,600 children aged <18 years and 8,476 children aged 6--23 months enrolled in 1 of 5
health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks
after
inactivated influenza vaccination, compared with control periods 3--4 weeks before and after vaccination
(175). In a study of 791 healthy children
(66), postvaccination fever was noted among 11.5% of children aged 1--5 years, 4.6% among
children aged 6--10 years, and 5.1% among children aged 11--15 years. Among children with high-risk medical conditions, one
study of 52 children aged 6 months--4 years reported fever among 27% and irritability and insomnia among 25%
(75); and a study among 33 children aged 6--18 months reported that one child had irritability and one had a fever and seizure after
vaccination (176). No placebo comparison was made in these studies. However, in pediatric trials of
A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection,
although the vaccine was associated with mild local tenderness or erythema
(74).

Limited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse
Event Reporting System (VAERS). During January 1,
1991--January 23, 2003, VAERS received 1,072 reports of adverse
events among children aged <18 years, including 174 reports of adverse events among children aged 6--23 months. The number
of influenza vaccine doses received by children during this time period is unknown. The most frequently reported events
among children were fever, injection-site reactions, and rash (unpublished data, CDC, 2003). Because of the limitations
of spontaneous reporting systems, determining causality for specific types of adverse events, with the exception of
injection-site reactions, is usually not possible by using VAERS data alone.

Immediate --- presumably allergic --- reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis)
rarely occur after influenza vaccination
(177). These reactions probably result from hypersensitivity to certain vaccine
components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only
a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have
severe egg allergy. Persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress
or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should
be administered. Persons who have documented immunoglobulin
E (IgE)-mediated hypersensitivity to eggs, including those
who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions
to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for
safely administering influenza vaccine to persons with egg allergies
(178--180).

Hypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal
can lead to induction of hypersensitivity, the majority of
patients do not have reactions to thimerosal when it is administered as
a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity
(181,182). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed type hypersensitivity reactions
(181).

Guillain-Barré Syndrome

The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barré syndrome (GBS)
(183,184). Among persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was
<10 cases/1 million persons vaccinated with the risk for influenza vaccine-associated GBS higher among persons aged
>25 years than persons <25 years
(183). Evidence for a causal relation of GBS with subsequent vaccines prepared from other
influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a
rare condition as GBS, which has an annual incidence of 10--20 cases/1 million adults
(185), and stretches the limits of epidemiologic investigation. More definitive data probably will require using other methodologies (e.g.,
laboratory studies of the pathophysiology of GBS).

During three of four influenza seasons studied during 1977--1991, the overall relative risk estimates for GBS after
influenza vaccination were slightly elevated but were not statistically significant in any of these studies
(186--188). However, in a study of the 1992--93 and 1993--94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0--2.8; p = 0.04) during the
6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The
combined number of GBS cases peaked 2 weeks after vaccination
(189). Thus, investigations to date indicate no substantial increase
in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine
does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. Cases of GBS after
influenza infection have been reported, but no epidemiologic studies have documented such an association
(190,191). Substantial evidence exists that multiple infectious illnesses, most notably
Campylobacter jejuni, as well as upper respiratory tract
infections are associated with GBS
(185,192--194).

Even if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately
1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which could be prevented
by vaccination among all age groups, especially persons aged
>65 years and those who have medical indications for
influenza vaccination (Table 1) (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccination
in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing
vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age
(185,195). No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated.

The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially
greater likelihood of subsequently experiencing GBS than persons without such a history
(186,196). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is
expected to be greater among persons with a history of
GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk
for recurrence of GBS is unknown; therefore, avoiding vaccinating persons who are not at high risk for severe
influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is
prudent. As an alternative, physicians might consider using influenza
antiviral chemoprophylaxis for these persons. Although data
are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications
from influenza, the established benefits of influenza vaccination justify yearly vaccination.

Simultaneous Administration of Other Vaccines, Including Childhood Vaccines

Adult target groups for influenza and pneumococcal polysaccharide vaccination overlap considerably
(197). For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly
consider administering pneumococcal polysaccharide and
inactivated influenza vaccines concurrently. Both vaccines can
be administered at the same time at different sites without increasing side effects
(198,199). However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not. A patient's verbal history is acceptable for determining
prior pneumococcal vaccination status. When indicated, pneumococcal vaccine should be administered to patients who
are uncertain regarding their vaccination history
(197).

No studies regarding the simultaneous administration of inactivated influenza vaccine and other childhood vaccines
have been conducted. However, inactivated vaccines usually do not interfere with the immune response to other inactivated or
live vaccines (62) and children at high risk for
influenza-related complications, including those aged 6--23 months, can
receive influenza vaccine at the same time they receive other routine vaccinations.

Strategies for Implementing These Recommendations in Health-Care Settings

Successful vaccination programs combine publicity and education for health-care workers and other potential
vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, and efforts to remove administrative
and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs
(19,200). Using standing orders programs is recommended for long-term care facilities (e.g., nursing homes and skilled nursing
facilities), hospitals, and home health agencies to ensure the administration of recommended vaccinations for adults
(201). Standing orders programs for both influenza and
pneumococcal vaccination should be conducted under the
supervision of a licensed practitioner according to a
physician-approved facility or agency policy by health-care personnel trained to screen patients
for contraindications to vaccination, to administer vaccine, and to monitor for
adverse events. A rule from the Centers for Medicare and Medicaid Services (CMS) recently removed the physician signature requirement for the administration
of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term care facilities, and
home health agencies (201). To the extent allowed by local and state law, these
facilities and agencies may implement standing
orders for influenza and pneumococcal vaccination of Medicare- and Medicaid-eligible patients. Other settings (e.g.,
outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces)
are encouraged to introduce standing orders programs as well
(20). Persons for whom influenza vaccine is recommended can
be identified and vaccinated in the settings described in the
following sections.

Outpatient Facilities Providing Ongoing Care

Staff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health
clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label
the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in
September and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the
medical record. Patients for whom vaccination is recommended who do not have regularly scheduled visits during the fall should
be reminded by mail, telephone, or other means of the need for vaccination.

Outpatient Facilities Providing Episodic or Acute Care

Beginning each September, acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer
vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain
the vaccine. This written information should be available in languages appropriate for the populations served by the facility.

Nursing Homes and Other Residential Long-Term Care Facilities

During October and November each year, vaccination should be routinely provided to all residents of chronic-care
facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a
family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one
time, preceding the influenza season. Residents admitted through March after completion of the facility's vaccination
program should be vaccinated at the time of admission.

Acute-Care Hospitals

Persons of all ages (including children) with high-risk conditions and persons aged
>50 years who are hospitalized at any time during September--March should be offered and strongly encouraged to receive influenza vaccine before they
are discharged. In one study, 39%--46% of patients hospitalized during the winter with influenza-related diagnoses had
been hospitalized during the preceding autumn
(202). Thus, the hospital serves as a setting in which persons at increased risk
for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after
their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before
admission, 1.9% during admission, and 10.6% after admission
(203). Using standing orders in hospitals increases vaccination
rates among hospitalized persons (204).

Visiting Nurses and Others Providing Home Care to Persons at High Risk

Beginning in September, nursing care plans should identify patients for whom vaccination is recommended, and
vaccine should be administered in the home, if necessary. Caregivers and other persons in the household (including children)
should be referred for vaccination.

Other Facilities Providing Services to Persons Aged
>50 Years

Beginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should
offer unvaccinated residents and attendees vaccination on-site before the influenza season. Staff education should emphasize
the need for influenza vaccine.

Health-Care Personnel

Beginning in October each year, health-care facilities should offer influenza vaccinations to all personnel, including
night and weekend staff. Particular emphasis should be placed on providing vaccinations for persons who care for members
of groups at high risk. Efforts should be made to educate health-care personnel regarding the benefits of vaccination and
the potential health consequences of influenza illness for themselves and their patients. Measures should be taken to provide
all health-care personnel convenient access to influenza vaccine at the work site, free of charge, as part of employee
health programs.

Inactivated Influenza Vaccine Supply

In 2000, difficulties with growing and processing the influenza A (H3N2) vaccine strain and other manufacturing
problems resulted in substantial delays in distribution of 2000--01 influenza vaccine, and fewer vaccine doses were available than
had been distributed in 1999 (205). In 2001, a less severe delay occurred, although, by December 2001, approximately
87.7 million doses of vaccine were produced, more than in any year except the 1976--77 swine influenza vaccine
campaign (206,207). During 2002, approximately 95 million doses were produced by the end of November, and approximately
12 million doses remained unsold by the vaccine manufacturers. For 2003, only two companies will be producing
influenza vaccine for the U.S. market (Aventis Pasteur, Inc., and Evans Vaccines, Ltd.), in comparison with 2002, when three
companies manufactured influenza vaccine for the U.S.
market.

Influenza vaccine delivery delays or vaccine shortages
remain possible in part because of the inherent critical time
constraints in manufacturing the vaccine given the annual
updating of the influenza vaccine strains. Steps being taken to address
possible future delays or vaccine shortages include identification and implementation of ways to expand the influenza vaccine
supply, improvement of targeted delivery of vaccine to groups at high risk when delays or shortages are expected, and
encouragement of the continued administration of vaccine beyond November and throughout the influenza season (December--March)
every year (see Timing of Annual Vaccination with Inactivated Influenza Vaccine).

Live, Attenuated Intranasal Influenza Vaccine

Intranasally administered, cold-adapted, live, attenuated, influenza virus vaccines (LAIVs) are being used in Russia and
have been under development in the United States since the 1960s
(208--212). LAIVs have been studied as monovalent,
bivalent, and trivalent formulations
(211,212). LAIVs consist of live viruses that replicate in the upper respiratory tract, that
induce minimal symptoms (i.e., are attenuated), and that replicate poorly at temperatures in the lower respiratory tract (i.e.,
are temperature-sensitive). Possible advantages of LAIVs are their potential to induce a broad mucosal and
systemic immune response, their ease of administration, and the
acceptability of an intranasal rather than intramuscular route
of administration. In a 5-year study that compared trivalent inactivated vaccine and bivalent LAIVs (administered by nose
drops) and that used related but different vaccine strains, the two vaccines were determined to be approximately equivalent in
terms of effectiveness (66,213). In a 1996--97 study of children aged 15--71 months, an intranasally administered trivalent
LAIV was 93% effective in preventing culture-positive influenza A (H3N2) and B infections, reduced febrile otitis media
among vaccinated children by 30%, and reduced otitis media with concomitant antibiotic use by 35% compared with
unvaccinated children (214). In a follow-up study during the 1997--98 season, the trivalent LAIV was 86% effective in preventing
culture-positive influenza among children, despite a suboptimal match between the vaccine's influenza A (H3N2) component and
the predominant circulating influenza A (H3N2) virus
(215). A study conducted among healthy adults during the same
season reported a 9%--24% reduction in febrile respiratory illnesses and 13%--28% reduction in lost work days
(216). No study has directly compared the efficacy or effectiveness of trivalent inactivated vaccine and trivalent LAIV. An application for
licensure of a LAIV is under review by FDA.

Recommendations for Using Antiviral Agents for Influenza

Antiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. However,
these agents are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United
States: amantadine, rimantadine, zanamivir, and oseltamivir.

Amantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza
A viruses but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2)
infection and was later approved in 1976 for the treatment and chemoprophylaxis of influenza type A virus infections among adults
and children aged >1 years. Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A
infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza
A infection among children, certain specialists in the management of influenza consider it appropriate for treatment of
influenza A among children (217).

Zanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors and that have
activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating
uncomplicated influenza infections. Zanamivir is approved for treating persons aged
>7 years, and oseltamivir is approved for treatment
for persons aged >1 years. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged
>13 years.

The four drugs differ in terms of their pharmacokinetics, side effects, routes of administration, approved age
groups, dosages, and costs. An overview of the indications, use,
administration, and known primary side effects of these medications
is presented in the following sections. Information contained in this report might not represent FDA approval or
approved labeling for the antiviral agents described. Package inserts should be consulted for additional information.

Role of Laboratory Diagnosis

Appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. The early diagnosis
of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However,
because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered
and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.

Influenza surveillance information as well as diagnostic testing can aid clinical judgment and help guide treatment
decisions. The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness
caused by other pathogens can overlap considerably with influenza
(29,33,34). Influenza surveillance by state and local
health departments and CDC can provide information
regarding the presence of influenza viruses in the community. Surveillance
can also identify the predominant circulating types, subtypes, and strains of influenza.

Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction
(PCR) and immunofluorescence (24). Sensitivity and specificity of any test for influenza might vary by the laboratory that
performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or
rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens
(218). As with any diagnostic test, results should be evaluated in the context of other clinical information available to the physician.

Commercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect
influenza viruses within 30 minutes (24,219). These rapid tests differ in the types of influenza viruses they can detect and whether
they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and
B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. The types
of specimens acceptable for use (i.e., throat swab, nasal wash, or nasal swab) also vary by test. The specificity and, in
particular, the sensitivity of rapid tests are lower than for viral culture and vary by test
(220,221). Because of the lower sensitivity of
the rapid tests, physicians should consider confirming negative tests with viral culture or other means. Further, when
interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the
context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should
be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning
diagnostic testing is located at http://www.cdc.gov/ncidod/diseases/flu/flu_dx_table.htm.

Despite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only
culture isolates can provide specific information regarding circulating influenza subtypes and strains. This information is needed
to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment
and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence
of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.

Indications for Use

Treatment

When administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce
the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of
uncomplicated influenza A and B illness by approximately 1 day, compared with placebo
(70,222--236). More clinical data are
available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza
B
infection (224--235,237--240). However, in vitro data and studies of treatment among mice and ferrets
(241--248), in addition to clinical studies have documented that zanamivir and oseltamivir have activity against influenza B viruses
(228,232--234,239,240).

None of the four antiviral agents has been demonstrated to be effective in preventing serious influenza-related
complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four
antiviral drugs is based principally on studies of patients with uncomplicated influenza
(249). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among
persons at high risk for serious complications of influenza
(27,222,224,225,227,228,235,250--254). Fewer studies of the efficacy
of influenza antivirals have been conducted among pediatric populations, compared with adults
(222,225,231,232,251,255,256). One study of oseltamivir treatment documented a decreased incidence of otitis media among children
(232). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year
(221).

To reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza
A illness should be discontinued as soon as clinically warranted, typically after 3--5 days of treatment or within 24--48
hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or
oseltamivir is 5 days.

Chemoprophylaxis

Chemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in the prevention
and control of influenza. Both amantadine and rimantadine are indicated for the chemoprophylaxis of influenza A infection,
but not influenza B. Both drugs are approximately 70%--90% effective in preventing illness from influenza A
infection (70,222,251). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection
and development of protective antibody against circulating influenza viruses. Therefore, certain persons who take these drugs
will develop protective immune responses to circulating
influenza viruses. Amantadine and rimantadine do not interfere with
the antibody response to the vaccine (222). Both drugs have been studied extensively among nursing home populations as
a component of influenza outbreak-control programs, which can limit the spread of influenza within chronic care
institutions (222,250,257--259).

Among the neuraminidase inhibitor antivirals, zanamivir and oseltamivir, only oseltamivir has been approved
for prophylaxis, but community studies of healthy adults indicate that both drugs are similarly effective in preventing
febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%)
(260--262). Both antiviral agents have also been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member
was diagnosed with influenza (239,262,263). Experience with prophylactic use of these agents in institutional settings or
among patients with chronic medical conditions is limited in comparison with the adamantanes
(234,253,254,264--266). One 6-week study of oseltamivir prophylaxis among nursing home residents reported a 92% reduction in influenza illness
(234,267). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine
(233,268). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among
severely immunocompromised persons.

When determining the timing and duration for administering influenza antiviral medications for prophylaxis, factors
related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must
be taken each day for the duration of influenza activity in the community. However, to be most
cost-effective, one study of amantadine or rimantadine prophylaxis reported that the drugs should be taken only during the period of peak
influenza activity in a community (269).

Persons at High Risk Who Are Vaccinated After Influenza Activity Has
Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, the development
of antibodies in adults after vaccination takes approximately 2 weeks
(159,160). When influenza vaccine is administered
while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time
from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can
require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of
prophylaxis after the second dose).

Persons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk
during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for
unvaccinated
persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of
hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by
a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should be considered for all
such persons, regardless of their vaccination status.

Persons Who Have Immune Deficiencies. Chemoprophylaxis can be considered for persons at high risk who
are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with
HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of
chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should
be monitored closely if chemoprophylaxis is
administered.

Other Persons. Chemoprophylaxis throughout the influenza season or during peak influenza activity might be
appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis can also be offered to persons who wish to
avoid influenza illness. Health-care providers and patients should make this decision on an individual basis.

Control of Influenza Outbreaks in Institutions

Using antiviral drugs for treatment and prophylaxis of
influenza is a key component of influenza outbreak control
in institutions. In addition to antiviral medications, other
outbreak-control measures include instituting droplet precautions
and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to
unvaccinated staff and patients, restricting staff movement
between wards or buildings, and restricting contact between ill staff or visitors
and patients (270--272) (for additional information
regarding outbreak control in specific settings, refer to additional references
in Additional Information Regarding Influenza Infection Control Among Specific
Populations).

The majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are
based on studies of influenza A outbreaks among nursing home populations where amantadine or rimantadine were
used (222,250,257--259,269). Less information is available concerning use of neuraminidase inhibitors in influenza A or
B institutional outbreaks
(253,254,266,267,273). When confirmed or suspected outbreaks of influenza occur in institutions
that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In
these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice
can substantially expedite administration of antiviral
medications.

When outbreaks occur in institutions, chemoprophylaxis should be administered to all residents, regardless of whether
they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If
surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end
of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered
to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless
of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine.

In addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other
closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). For
example, chemoprophylaxis with rimantadine has been used successfully to control an influenza A outbreak aboard a large cruise
ship (151).

To limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or
acute-care settings or other closed settings, measures should be taken to reduce contact as much as possible between persons
taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant
Strains of Influenza).

Dosage

Dosage recommendations vary by age group and medical conditions (Table 4).

Children

Amantadine. Use of amantadine among children aged
<1 year has not been adequately evaluated. The
FDA-approved dosage for children aged 1--9 years for treatment and prophylaxis is 4.4--8.8 mg/kg/day, not to exceed 150 mg/day.
Although further studies are needed to determine the optimal dosage for children aged 1--9 years, physicians should consider
prescribing
only 5 mg/kg/day (not to exceed 150 mg/day) to reduce
the risk for toxicity. The approved dosage for children aged
>10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day,
regardless of age, is advisable (252).

Rimantadine. Rimantadine is approved for prophylaxis among children aged
>1 years and for treatment and
prophylaxis among adults. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in
the management of influenza consider it appropriate for treatment among children
(217). Use of rimantadine among children aged <1 year has not been adequately evaluated. Rimantadine should be administered in 1 or 2 divided doses at a dosage of
5 mg/kg/day, not to exceed 150 mg/day for children aged 1--9 years. The approved dosage for children aged
>10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day,
regardless of age, is recommended (274).

Zanamivir. Zanamivir is approved for treatment among children aged
>7 years. The recommended dosage of zanamivir
for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice
daily (approximately 12 hours apart) (233).

Oseltamivir. Oseltamivir is approved for treatment among persons aged
>1 year and for chemoprophylaxis among
persons age >13 years. Recommended treatment dosages for children vary by the weight of the child: the dosage recommendation
for children who weigh <15 kg is 30 mg twice a day; for children weighing >15--23 kg, the dosage is 45 mg twice a day; for
those weighing >23--40 kg, the dosage is 60 mg twice a day; and for children weighing >40 kg, the dosage is 75 mg twice a day.
The treatment dosage for persons aged >13 years is 75 mg twice daily. For children aged
>13 years, the recommended dose for prophylaxis is 75 mg once a day
(234).

Persons Aged >65 Years

Amantadine. The daily dosage of amantadine for persons aged
>65 years should not exceed 100 mg for prophylaxis
or treatment, because renal function declines with increasing age. For certain older persons, the dose should be further reduced.

Rimantadine. Among older persons, the incidence and
severity of central nervous system (CNS) side effects are
substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted
for estimated renal clearance (275). However, chronically ill older persons have had a higher incidence of CNS
and gastrointestinal symptoms and serum concentrations 2--4 times higher than among healthy, younger persons
when rimantadine has been administered at a dosage of 200 mg/day
(222).

For prophylaxis among persons aged >65 years, the recommended dosage is 100 mg/day. For treatment of older persons
in the community, a reduction in dosage to 100 mg/day should be considered if they experience side effects when taking a
dosage of 200 mg/day. For treatment of older nursing home residents, the dosage of rimantadine should be reduced to 100
mg/day (274).

Zanamivir and Oseltamivir. No reduction in dosage is
recommended on the basis of age alone.

Persons with Impaired Renal Function

Amantadine. A reduction in dosage is recommended for patients with creatinine clearance
<50 mL/min/1.73m2. Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Because recommended dosages
on the basis of creatinine clearance might provide only an approximation of the optimal dose for a given patient, such
persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the
drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance
(276,277).

Rimantadine. A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance <10
mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal
insufficiency, including older persons, should be monitored for adverse
effects, and either the dosage should be reduced or the drug
should be discontinued, if necessary. Hemodialysis
contributes minimally to drug clearance
(278).

Zanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired
renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in
renal clearance, increases in half-life, and increased systemic exposure to zanamivir were observed
(233,279). However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels
of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at
the recommended dose (280,281). On the basis of these considerations, the manufacturer recommends no dose adjustment
for
inhaled zanamivir for a 5-day course of treatment for
patients with either mild to moderate or severe impairment in
renal function (233).

Oseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase
with declining renal function (234,238). For patients with creatinine clearance of 10--30 mL/min
(234), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the prophylaxis dosage to 75 mg every other day is
recommended. No treatment or prophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.

Persons with Liver Disease

Amantadine. No increase in adverse reactions to amantadine has been observed among persons with liver disease.
Rare instances of reversible elevation of liver enzymes among
patients receiving amantadine have been reported, although a
specific relation between the drug and such changes has not been established
(282).

Rimantadine. A reduction in dosage to 100 mg/day is
recommended for persons with severe hepatic dysfunction.

Zanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction.

Persons with Seizure Disorders

Amantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders
who have received amantadine (283). Patients with seizure disorders should be observed closely for possible
increased seizure activity when taking amantadine.

Rimantadine. Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were
not receiving anticonvulsant medication while taking rimantadine
(284). The extent to which rimantadine might increase
the incidence of seizures among persons with seizure disorders has not been adequately evaluated.

Zanamivir and Oseltamivir. Seizure events have been
reported during postmarketing use of zanamivir and
oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.

Route

Amantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet
or syrup form, and oseltamivir is available in capsule or oral suspension form
(209,210). Zanamivir is available as a dry
powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients
will benefit from instruction and demonstration of correct use of this device
(233).

Pharmacokinetics

Amantadine

Approximately 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular
secretion (257,285--288). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency,
and dosages might need to be decreased (see Dosage) (Table 4).

Rimantadine

Approximately 75% of rimantadine is metabolized by the liver
(251). The safety and pharmacokinetics of
rimantadine among persons with liver disease have been evaluated only after single-dose administration
(251,289). In a study of persons with chronic liver disease (the majority with stabilized cirrhosis), no alterations in liver function were observed after a
single dose. However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than
that reported for persons without liver disease
(274).

Rimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine
among patients with renal insufficiency have been evaluated only
after single-dose administration (251,278). Further studies
are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency.
In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40%
lower,
and the elimination half-life was approximately 1.6-fold greater than that among healthy persons of the same age
(278). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was
also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the
same weight, age, and sex (274,290).

Zanamivir

In studies of healthy volunteers, approximately 7%--21% of the orally inhaled zanamivir dose reached the lungs, and
70%--87% was deposited in the oropharynx
(233,291). Approximately 4%--17% of the total amount of orally inhaled zanamivir
is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5--5.1 hours and is excreted
unchanged in the urine. Unabsorbed drug is excreted in the feces
(233,281).

Oseltamivir

Approximately 80% of orally administered oseltamivir is absorbed systemically
(238). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase
inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has
a half-life of 6--10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic
pathway (234,292). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion
(292).

Side Effects and Adverse Reactions

When considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of
therapy), clinicians must consider the patient's age, weight, and renal function (Table 4); presence of other medical
conditions; indications for use (i.e., prophylaxis or therapy); and the
potential for interaction with other medications.

Amantadine and Rimantadine

Both amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young,
healthy adults at equivalent dosages of 200 mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety,
insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those
taking rimantadine (293). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants
taking rimantadine at a dosage of 200 mg/day experienced
>1 CNS symptom, compared with approximately 13% of those taking
the same dosage of amantadine and 4% of those taking placebo
(293). A study of older persons also demonstrated fewer CNS
side effects associated with rimantadine compared with amantadine
(275). Gastrointestinal side effects (e.g., nausea and
anorexia) occur in approximately 1%--3% of persons taking either drug, compared with 1% of persons receiving the placebo
(293).

Side effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug.
Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have
been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures)
(276,283). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons
who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among older persons who have been
taking amantadine as prophylaxis at a dosage of 200 mg/day
(257). Clinical observations and studies have indicated that lowering
the dosage of amantadine among these persons reduces the incidence and severity of such side effects
(Table 4). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported
(276). Because rimantadine has been marketed for a shorter period than amantadine, its safety among certain patient
populations (e.g., chronically ill and older persons) has been evaluated less frequently. Because amantadine has anticholinergic effects
and might cause mydriasis, it should not be used in patients with untreated angle closure glaucoma
(276).

Zanamivir

In a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive
pulmonary disease where study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14%
of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in
1 second (FEV1) after treatment (233,235). However, in a phase-I study of persons with mild or moderate asthma who did
not
have influenza-like illness, 1 of 13 patients experienced bronchospasm after administration of zanamivir
(233). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been
reported. Certain patients had underlying airways disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk
for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is
not recommended for treatment for patients with underlying airway disease
(233). If physicians decide to prescribe zanamivir
to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should
be used with caution under conditions of appropriate monitoring and supportive care, including the availability of
short-acting bronchodilators (249). Patients with asthma or chronic
obstructive pulmonary disease who use zanamivir are advised to
1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact
their physician if they experience difficulty breathing
(233). No definitive evidence is available regarding the safety or efficacy
of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of
acute influenza (249). Allergic reactions, including oropharyngeal or facial edema, have also been reported during
postmarketing surveillance (233,253).

In clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar
for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone)
(223--228,253). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis;
cough; headache; dizziness; and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in
the clinical treatment studies combined
(233).

Oseltamivir

Nausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea
without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without
vomiting, approximately 6%; vomiting, approximately 3%)
(229,230,234,294). Among children treated with oseltamivir, 14.3%
had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect
(232), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment
because of these symptoms (234). Similar types and rates of adverse events were reported in studies of oseltamivir prophylaxis
(234). Nausea and vomiting might be less severe if oseltamivir is taken with food
(234,294).

Use During Pregnancy

No clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir,
or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester
have been reported (124,125). However, both amantadine and rimantadine have been demonstrated in animal studies to
be teratogenic and embryotoxic when administered at substantially high doses
(274,276). Because of the unknown effects
of influenza antiviral drugs on pregnant women and their
fetuses, these four drugs should be used during pregnancy only if
the potential benefit justifies the potential risk to the
embryo or fetus (see manufacturers' package inserts)
(233,234,274,276).

Drug Interactions

Careful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including
CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse
CNS reactions (222). No clinically substantial
interactions between rimantadine and other drugs have been identified.

Clinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have
been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro data and data from
studies using rats (233,295).

Limited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and
oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a
potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and
probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate
twofold increase in the plasma levels of oseltamivir carboxylate
(234,292).

No published data are available concerning the safety or efficacy of using combinations of any of these four
influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral
drugs, package inserts should be consulted.

Antiviral Drug-Resistant Strains of Influenza

Amantadine-resistant viruses are cross-resistant to rimantadine and vice versa
(296). Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy
(256,297,298). During the course of amantadine or rimantadine therapy,
resistant influenza strains can replace sensitive strains within 2--3 days
of starting therapy (297,299). Resistant viruses have been isolated from persons who live at home or in an institution where
other residents are taking or have recently taken amantadine or rimantadine as therapy
(300,301); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown.
Amantadine- and rimantadine-resistant viruses are not more virulent or transmissible than sensitive viruses
(302). The screening of epidemic strains of influenza A has rarely detected amantadine- and rimantadine-resistant viruses
(297,303,304).

Persons who have influenza A infection and who are treated with either amantadine or rimantadine can shed
sensitive viruses early in the course of treatment and later shed drug-resistant viruses, including after 5--7 days of therapy
(256). Such persons can benefit from therapy even when resistant viruses emerge.

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro
(305--312), but induction of resistance requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can
be induced with fewer passages in cell culture
(313,314). Development of viral resistance to zanamivir and oseltamivir
during treatment has been identified but does not appear to be frequent
(234,315--318). In clinical treatment
studies using oseltamivir, 1.3% of posttreatment isolates from patients aged
>13 years and 8.6% among patients aged 1--12 years
had decreased susceptibility to oseltamivir
(234). No isolates with reduced susceptibility to zanamivir have been reported
from clinical trials, although the number of posttreatment isolates tested is limited
(319) and the risk for emergence of
zanamivir-resistant isolates cannot be quantified
(233). Only one clinical isolate with reduced susceptibility to zanamivir, obtained
from an immunocompromised child on prolonged therapy, has been reported
(316). Available diagnostic tests are not optimal
for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being
developed (319,320). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted
(321).

Sources of Information Regarding Influenza and Its Surveillance

Information regarding influenza surveillance, prevention, detection, and control is available on the
CDC/National Center for Infectious Diseases website at http://www.cdc.gov/ncidod/diseases/flu/weekly.htm. Surveillance information
is available through the CDC Voice Information System (influenza update) at 888-232-3228 or CDC Fax Information Service
at 888-232-3299. During October--May, surveillance information is updated at least every other week. In addition,
periodic updates regarding influenza are published in the
MMWR Weekly. Additional information regarding influenza vaccine can be
obtained at the CDC/National Immunization Program website at http://www.cdc.gov/nip/flu
or by calling their hotline
at 800-232-2522 (English) or 800-232-0233 (Spanish). State and local health departments should be consulted
concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, and
for reporting influenza outbreaks and receiving advice concerning outbreak control.

Each year, ACIP provides general, annually updated information regarding control and prevention of influenza.
Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised
persons, health-care personnel, hospitals, and travelers) are also available in the following publications:

CDC. General recommendations on immunization:
recommendations of the Advisory Committee on
Immunization Practices (ACIP) and the American Academy of Family Practitioners (AAFP). MMWR 2002;51(No. RR-2):1--35.

Bodnar UR, Maloney SA, Fielding KL, et al. Preliminary guidelines for the prevention and control of influenza-like
illness among passengers and crew members on cruise ships. Atlanta, GA: US Department of Health and
Human Services, CDC, National Center for Infectious Diseases, 1999.

CDC. General recommendations for preventing influenza A infection among travelers. Atlanta, GA: US Department of Health and Human Services, CDC, 2001. Available at http://www.cdc.gov/travel/feb99.htm.

US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA). USPHS/IDSA Prevention
of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic
infections in persons infected with human immunodeficiency virus. Final November 28, 2001;1--65. Available at
http://www.aidsinfo.nih.gov.

US Department of Health and Human Services, PHS. Healthy people 2000: national health promotion and disease prevention objectives---full
report, with commentary. Washington, DC: US Department of Health and Human Services, Public Health Service, 1991.

Irving WL, James DK, Stephenson T, et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical
and seroepidemiological study. British Journal of Obstetrics and Gynaecology 2000;107:1282--9.

Fine AD, Bridges CB, De Guzman AM, et al. Influenza A among patients with human immunodeficiency virus: an outbreak of infection at
a residential facility in New York City. Clin Infect Dis 2001;32:1784--91.

MIST (Management of Influenza in the Southern Hemishpere Trialists). Randomised trial of efficacy and safety of inhaled zanamivir in treatment
of influenza A and B virus infections. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study
Group. Lancet 1998;352:1877--81.

Hendrick JA, Barzilai A, Behre U. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age:
a randomized controlled trial. Pediatr Infect Dis J 2000;19:410--7.

Woods JM, Bethell RC, Coates JA, et al. 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of
the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother 1993;37:1473--9.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of
Health and Human Services.References to non-CDC sites on the Internet are
provided as a service to MMWR readers and do not constitute or imply
endorsement of these organizations or their programs by CDC or the U.S.
Department of Health and Human Services. CDC is not responsible for the content
of pages found at these sites. URL addresses listed in MMWR were current as of
the date of publication.

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